This invention relates to prostaglandin agonists, pharmaceutical compositions containing such agonists and the use of such agonists to prevent bone loss or restore or augment bone mass and to enhance bone healing including the treatment of conditions which present with low bone mass and/or bone defects in vertebrates, and particularly mammals, including humans.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study has estimated that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
There are currently two main types of pharmaceutical therapy for the treatment of osteoporosis. The first is the use of anti-resorptive compounds to reduce the resorption of bone tissue.
Estrogen is an example of an anti-resorptive agent. It is known that estrogen reduces fractures. In addition, Black, et al. in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises those of the beneficial high density lipoproteins (HDL""s). However, estrogen failed to restore bone back to young adult levels in the established osteoporotic skeleton. Furthermore, long-term estrogen therapy, has been implicated in a variety of disorders including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable effect on serum LDL but do not cause undesirable effects.
A second type of pharmaceutical therapy for the treatment of osteoporosis is the use of anabolic agents to promote bone formation and increase bone mass. This class of agents is expected to restore bone to the established osteoporosis skeleton.
U.S. Pat. No. 4,112,236 discloses certain interphenylene 8-aza-9-dioxothia-11,12-secoprostaglandins for the treatment of patients with renal impairment.
Certain prostaglandin agonists are disclosed in GB 1478281, GB1479156 and U.S. Pat. Nos. 4,175,203, 4,055,596, 4,175,203, 3,987,091 and 3,991,106 as being useful as, for example, renal vasodilators.
U.S. Pat. No. 4,033,996 discloses certain 8-aza-9-oxo(and dixox)-thia-11,12-secoprostanglandins which are useful as renal vasodilators, for the prevention of thrombus formation, to induce growth hormone release, and as regulators of the immune response.
French patent no. 897,566 discloses certain amino acid derivatives for the treatment of neurological, mental or cardiovascular disease.
J. Org. Chem. 26; 1961; 1437 discloses N-acetyl-N-benzyl-p-aminophenylmercaptoacetic acid.
U.S. Pat. No. 4,761,430 discloses certain arylbenzenesulfonamide compounds as lipid-lowering agents.
U.S. Pat. No. 4,443,477 discloses certain sulphonamidophenylcarboxylic acids as lipid lowering agents.
U.S. Pat. No. 3,528,961 discloses certain xcex5-caprolactam derivatives as dyes.
U.S. Pat. No. 3,780,095 discloses certain acylated anilinocarboxylic acids as choleretics.
U.S. Pat. No. 4,243,678 discloses certain acylhydrocarbylaminoalkanoic acids as having utility in the treatment of gastric ulcers, as sebaceous gland excretion inhibitors and for combatting skin inflammation.
U.S. Pat. No. 4,386,031 discloses certain N-benzoyl-xcfx89-anilinoalkanecarboxylic acids as antiallergic agents, thrombotic aggregation inhibitors, antiinflammatory agents and lipid-lowering agents.
In addition to osteoporosis, approximately, 20-25 million women and an increasing number of men have detectable vertebral fractures as a consequence of reduced bone mass, with an additional 250,000 hip fractures reported yearly in America alone. The latter case is associated with a 12% mortality rate within the first two years and with a 30% rate of patients requiring nursing home care after the fracture. While this is already significant, the economic and medical consequences of convalescence due to slow or imperfect healing of these bone fractures is expected to increase, due to the aging of the general population.
Estrogens have been shown (Bolander et al., 38th Annual Meeting Orthopedic Research Society, 1992) to improve the quality of the healing of appendicular fractures. Therefore, estrogen replacement therapy might appear to be a method for the treatment of fracture repair. However, patient compliance with estrogen therapy is relatively poor due to its side effects, including the resumption of menses, mastodynia, an increased risk of uterine cancer, an increased perceived risk of breast cancer, and the concomitant use of progestins. In addition, men are likely to object to the use of estrogen treatment. The need exists for a therapy which would be beneficial to patients who have suffered debilitating bone fractures and which would increase patient compliance.
Although there are a variety of osteoporosis therapies, there is a continuing need and a continuing search in this field of art for alternative osteoporosis therapies. In addition, there is a need for bone fracture healing therapies. Also, there is need for a therapy which can promote bone re-growth into skeletal areas where defects exist such as defects caused or produced by, for example, tumors in bone. Further, their is a need for therapy which can promotes bone re-growth into skeletal areas where bone grafts are indicated.
This invention is directed to compounds having the Formula I 
prodrugs thereof, and the pharmaceutical acceptable salts of said compounds and prodrugs, wherein
A is SO2 or CO;
G is Ar, Ar1-V-Ar2, Ar-(C1-C6)alkylene, Ar-CONH-(C1-C6)alkylene, R1R2-amino, oxy(C1-C6)alkylene, amino substituted with Ar, or amino substituted with Ar(C1-C4)alkylene and R11, wherein R11 is H or (C1-C8)alkyl, R1 and R2 may be taken separately and are independently selected from H and (C1-C8)alkyl, or R1 and R2 are taken together with the nitrogen atom of the amino group to form a five- or six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom and optionally mono-, di- or tri-substituted independently with up to two oxo, hydroxy, (C1-C4)alkyl, fluoro or chloro;
B is N or CH;
Q is
-(C2-C6)alkylene-W-(C1-C3)alkylene-, said alkylenes each optionally substituted with up to four substitutes independently selected from fluoro or (C1-C4) alkyl,
-(C4-C8)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
-X-(C1-C5)alkylene-, said alkylene optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
-(C1-C5)alkylene-X-, said alkylene optionally substituted with up to four substituents independently selected fluoro or (C1-C4)alkyl,
-(C1-C3)alkylene-X-(C1-C3)alkylene, said alkylenes each optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
-(C2-C4)alkylene-W-X-(C0-C3)-alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl,
-(C0-C4)alkylene-X-W-(C1-C3)alkylene-, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl,
-(C2-C5)alkylene-W-X-W-(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other, said alkylenes each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl,
-(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-, said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl,
-(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X-(C0-C5)alkylene-, said alkylenes and said ethenylene each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl,
-(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X-W-(C1-C3)alkylene-, said alkylenes and said ethenylene optionally each substituted with up to four substitutes each independently selected from fluoro is (C1-C4)alkyl,
-(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl, or
-(C1-C4)alkylene-ethynylene-X-(C0-C3)alkylene-, said alkylenes and said ethynylene each optionally substituted with up to four substituents each independently selected from fluoro or (C1-C4)alkyl;
Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
K is a bond, (C1-C9)alkylene, thio(C1-C4)alkylene, (C1-C4)alkylenethio(C1-C4)alkylene, (C1-C4)alkyleneoxy(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C9)alkylene optionally mono-unsaturated and wherein, when K is not a bond, K is optionally mono-, di- or tri-substituted independently with chloro, fluoro, hydroxy or methyl;
M is xe2x80x94Ar3, xe2x80x94Ar4-V1-Ar5, xe2x80x94Ar4-Sxe2x80x94Ar5, xe2x80x94Ar4-SOxe2x80x94Ar5, xe2x80x94Ar4-SO2-Ar5 or xe2x80x94Ar4-Oxe2x80x94Ar5;
Ar is a partially saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicylic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur; or Ar is a fully saturated five to seven membered ring having one or two heteroatoms selected independently from oxygen, sulfur and nitrogen;
Ar1 and Ar2 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
said Ar, Ar1 and Ar2 moieties are optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R3, R4 and R5 wherein R3, R4 and R5 are independently hydroxy, nitro, halo, carboxy, (C1-C7)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C2-C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,Nxe2x80x2- or tri-N,N,Nxe2x80x2-(C1-C4)alkyl substituted aminocarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N or di-N,N-(C1-C4)alkylaminosulfinyl;
Ar3, Ar4 and Ar5 are each independently a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
said Ar3, Ar4 and Ar5 moieties are optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety independently selected from R31, R41 and R51 wherein R31, R41 and R51 are independently hydroxy, nitro, halo, carboxy, (C1-C7)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C2-C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, hydroxysulfonyl, aminocarbonylamino or mono-N-, di-N,N-, di-N,Nxe2x80x2- or tri-N,N,Nxe2x80x2-(C1-C4)alkyl substituted aminocarbonylamino, sulfonamide, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl;
W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, mono-N-(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, N-(C1-C4)alkylenesulfonylamino, craboxamido, N-(C1-C4)alkylenecarboxamido, carboxamidooxy, N-(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-N-(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines;
X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl;
R1, R2, R3, R4, R5, R11, R31, R41 and R51, when containing an alkyl, alkylene, alkenylene or alkynylene moiety, are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and
V and V1 are each independently a bond, thio(C1-C4)alkylene, (C1-C4)alkylenethio, (C1-C4)alkyleneoxy, oxy(C1-C4)alkylene or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro;
with the provisos that:
a. when K is (C2-C4)alkylene and M is Ar3 and Ar3 is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy; and
b. when K is a bond; G is phenyl, phenylmethyl, substituted phenyl or substituted phenylmethyl; Q is (C3-C8)alkylene; and M is Ar3 or Ar4-Ar5, then A is sulfonyl.
A preferred group of compounds, designated the A Group, comprises those compounds having the formula I as shown above, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein B is N; Z is carboxyl, (C1-C6)alkoxycarbonyl or tetrazolyl; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperindyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, cyclopentenyl, cyclohexenyl, benzo(b)thienyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, quniolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl and 1,4-benzodioxan; Ar1, Ar2, Ar3, Ar4 and Ar5 are each independently cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinylpiperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, qunioxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, 1,4-benzodioxan, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl; and X is tetrahydrofuranyl, phenyl, thiazolyl, thienyl, pyridyl, pyrrazolyl, furanyl or pyrimidyl, wherein X is optionally mono-, di- or tri-substituted independently with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein each of said Ar, Ar1 and Ar2 groups are optionally substituted on carbon or nitrogen with up to three substituents independently selected from R3, R4 and R5; each of said Ar, Ar1 and Ar2 groups are optionally substituted independently on carbon or sulfur with one or two oxo groups; each of said Ar3, Ar4 and Ar5 groups are optionally substituted on carbon or nitrogen independently with up to three R31, R41 and R51 groups and each of said Ar3, Ar4 and Ar5 groups are optionally substituted independently on carbon or sulfur with one or two oxo groups.
A group of compounds within the A Group, designated the B Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is oxy(C1-C6)alkylene; Q is
-(C2-C6)alkylene-O-(C1-C3)alkylene-,
-(C4-C8)alkylene-, said -(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
-X-(C2-C5)alkylene-,
-(C1-C5)alkylene-X-,
-(C1-C3)alkylene-X-(C1-C3)alkylene-,
-(C2-C4)alkylene-O-X-(C0-C3)alkylene-, or
-(C0-C4)alkylene-X-O-(C1-C3)alkylene; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
Another group of compounds which is preferred within the A Group, designated the C Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is Ar; Q is
-(C2-C6)alkylene-O-(C1-C3)alkylene-,
-(C4-C8)alkylene-, said -(C4-C8)alkylene- optionally substituted with up to substituents independently selected from fluoro or (C1-C4)alkyl,
-X-(C2-C5)alkylene-,
-(C1-C5)alkylene-X-,
-(C1-C3)alkylene-X-(C1-C3)alkylene-,
-(C2-C4)alkylene-O-X-(C0-C3)alkylene-, or
-(C0-C4)alkylene-X-O-(C1-C3)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
Another group of compounds which is preferred within the A Group, designated the D Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO, G is R1R2-amino or amino substituted with Ar, or amino substituted with Ar(C1-C4)alkylene and R11, wherein R11 is H; Q is
-(C2-C6)alkylene-O-(C1-C3)alkylene-,
-(C4-C8)alkylene-, said -(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
-X-(C2-C5)alkylene-,
-(C1-C5)alkylene-X-,
-(C1-C3)alkylene-X-(C1-C3)alkylene-,
-(C2-C4)alkylene-O-X-(C0-C3)alkylene-, or
-(C0-C4)alkylene-X-O-(C1-C3)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and
wherein R1 and R2 may be taken separately and are independently selected from H and (C1-C8)alkyl, or R1 and R2 are taken together to form a five- or six-membered azacycloalkyl, said axazcycloalkyl optionally containing an oxygen atom.
Another group of compounds which is preferred within the G Group, designated the E Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO2; G is R1R2-amino, or amino substituted with Ar and R11; Q is
-(C2-C6)alkylene-O-(C1-C3)alkylene-,
-(C4-C8)alkylene-, said -(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
xe2x80x94X-(C2-C5)alkylene-,
-(C1-C5)alkylene-X-,
-(C1-C3)alkylene-X-(C1-C3)alkylene-,
-(C2-C4)alkylene-)-O-X-(C0-C3)alkylene-, or
-(C0-C4)alkylene-X-O-(C1-C3)alkylene; and X phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and
wherein R1 and R2 may be taken separately and are independently selected from H and (C1-C8)alkyl, or R1 and R2 are taken together to form a five- or six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom.
Another group of compounds which is preferred within the A Group, designated the F Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO2; G is Ar, Ar(C1-C2)alkylene or Ar1-V-Ar2; Q is
-(C2-C6)alkylene-O-(C1-C3)alkylene-,
-(C4-C8)alkylene-, said -(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl,
-X-(C2-C5)alkylene-,
-(C1-C5)alkylene-X-,
-(C1-C3)alkylene-X-(C1-C3)alkylene-,
-(C2-C4)alkylene-O-X-(C0-C3)alkylene-, or
-(C0-C4)alkylene-X-O-(C1-C3)alkylene; and X is phenyl, pyrimidyl, pyridyl, thienyl, tetrahydrofuranyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
A particularly preferred group of compounds within the F Group, designated the FA Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein G is Ar or Ar-(C1-C2)-alkylene; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-thiadiazolyl wherein each of said Ar groups is optionally substituted on carbon or nitrogen with R1, R2 or R3; Ar4 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-trazinyl, azepinyl, oxepinyl or thiepinyl wherein each of said Ar4 groups is optionally mono- di- or tri-substituted on carbon on nitrogen with R31, R41 or R51; Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, primidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, 1,4-dioxanyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or thiepinyl wherein each of said Ar5 groups is optionally mono- di- or tri-substituted on carbon or nitrogen with R31, R41 or R51; Q is -(C5-C7)-alkylene-, -(C1-C2)-alkylene-X-(C1-C2)-alkylene-, -(C1-C2)-X-O-(C1-C2)-alkylene-, -(C2-C4)-alkylene-thienyl-, -(C2-C4)-alkylene-furanyl- or -(C2-C4)-alkylene-thiazolyl-; X is phenyl, pyridyl, pyrimidyl or thienyl; and said X groups are optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethoxy or methyl; said -(C2-C4)-alkylene-furanyl- and -(C2-C4)-alkylene-thienyl- having a 2,5-substitution pattern, e.g., 
A preferred group of compounds within the FA Group, designated the FB Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is methylene, M is Ar4-Ar5, Ar4-O-Ar5 or Ar4-S-Ar5 and Ar is phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally mono-, di- or tri-substituted on carbon or nitrogen with R3, R4 or R5.
A preferred group of compounds within the FB Group, designated the FC Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein M is Ar4-Ar5; Ar is phenyl, pyridyl or imidazolyl; Ar4 is phenyl, furanyl or pyridyl; and Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl, wherein Ar, Ar4 and Ar5 are optionally mono, -di- or tri-substituted on carbon or nitrogen independently with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy.
An especially preferred group of compounds within the FC Group, designated the FD Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C5-C7)alkylene-.
Another especially preferred group of compounds within the FC Group, designated the FE Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is CH2-X-CH2- and X is metaphenylene optionally mono- or di- substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
A preferred group of compounds within the FE Group are those compounds, and pharmaceutically acceptable salts and prodrugs thereof, selected from (3-(((pyridine-3-sulfonyl)-(4-pyrimidin-5-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((5-phenyl-furan-2-ylmethyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyrimidin-2-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; and (3-(((4-pyrazin-2-yl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
An especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5 wherein Ar4 is a furanyl ring and Ar5 is phenyl wherein said phenyl moiety is substituted at the 5-position of said furanyl ring; and Q is xe2x80x94CH2-X-CH2- wherein X is metaphenylene.
Another especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5 wherein Ar4 is phenyl and Ar5 is pyrimid-2-yl and said pyrimid-2-yl moiety is substituted at the 4-position of said phenyl ring; and Q is -CH2-X-CH2- wherein X is metaphenylene.
Yet another especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5 wherein Ar4 is phenyl and Ar5 is thiazol-2-yl and said thiazol-2-yl moiety is substituted at the 4-position of said phenyl ring; and Q is -CH2-X-CH2- wherein X is metaphenylene.
Yet another especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5 wherein Ar4 is phenyl and Ar5 is pyrimid-5-yl and said pyrimid-5-yl moiety is substituted at the 4-position of said phenyl ring; and Q is -CH2-X-CH2- wherein X is metaphenylene.
Yet another especially preferred compound within the FE Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4-Ar5 wherein Ar4 is phenyl and Ar5 is pyrazin-2-yl and said pyrazin-2-yl is substituted at the 4-position of said phenyl ring; and Q is xe2x80x94CH2-Xxe2x80x94CH2- wherein X is metaphenylene.
A preferred group of compounds within the FC Group, designated the G Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C2-C4)-alkylene-thienyl-, -(C2-C4)-alkylene-furanyl- or -(C2-C4)-alkylene-thiazolyl-.
An especially preferred compound within the G Group is 5-(3-((pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-propyl)-thiophene-2-carboxylic acid.
An especially preferred compound within the G Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is n-propylenyl; X is thienyl; Z is carboxy; Ar is 3-pyridyl; Ar4 is phenyl; and Ar5 is 2-thiazolyl; said 2-thiazolyl being substituted at the 4-position of said phenyl.
Another especially preferred group of compounds within the FC Group, designated the H Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-O-CH2; Ar4 is phenyl or pyridyl; said phenyl and pyridyl are optionally substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl and methyl; and X is metaphenylene.
A preferred group of compounds within the H Group are (3-(((4-cyclohexyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyridin-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyridin-3-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyridin-4-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; and (3-(((pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid.
An especially preferred compound within the H Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is cyclohexyl; and said cyclohexyl moiety is substituted at the 4-position of said phenyl ring.
Another especially preferred compound within the H Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is thiazol-2-yl; and said thiazol-2-yl moiety is substituted at the 4-position of said phenyl ring.
Yet another especially preferred compound within the H Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is 2-pyridyl; and said 2-pyridyl moiety is substituted at the 4-position of said phenyl ring.
Yet another especially preferred compound within the H Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is 3-pyridyl; and said 3-pyridyl moiety is substituted at the 4-position of said phenyl ring.
Yet another especially preferred compound within the H Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is 4-pyridyl; and said 4-pyridyl moiety is substituted at the 4-position of said phenyl ring.
A preferred group of compounds within the FA Group, designated the I Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is methylene, G is Ar; Ar is phenyl, pyridazinyl, pyrazolyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, Ar is optionally mono-, di- or tri-substituted with R3, R4 or R5, and M is Ar3, wherein said Ar3 is cyclopentyl, cyclohexyl, phenyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzo(b)thienyl, benzoxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, naphthyl, tetralinyl, 2H-1-benzopyranyl or 1,4-benzodioxan and is optionally mono-, di- or tri-substituted with R31, chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy.
An especially preferred group of compounds within the I Group are (3-(((dihydro-benzo[1,4]dioxin-6-ylmethyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; and (3-((benzofuran-2-ylmethyl-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
An especially preferred compound within the I Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compound and prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy; M is 6-(1,4-benzodioxan); and Q is -CH2-X-CH2- wherein X is metaphenylene.
Another especially preferred compound within the I Group is the compound wherein Ar is pyrid-3-yl; Z is carboxy; M is 2-benzofuryl; and Q is -CH2-X-CH2- wherein X is metaphenylene.
Another especially preferred group of compounds within the I Group, designated the J Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is phenyl, pyridyl or imidazolyl, said phenyl, pyridyl and imidazolyl optionally substituted independently with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; Ar3 is phenyl substituted with R31, wherein R31 is (C1-C7)alkyl, mono-N- or di-N, N-(C1-C4)alkylamine, or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and Ar3 is further optionally mono- or di-substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A preferred group of compounds within the J Group, designated the K Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said components and said prodrugs, wherein Q is -(C5-C7)alkylene-.
Another preferred group of compounds within the J Group, designated the L Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-CH2- and X is phenyl optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
An especially preferred group of compounds within the L Group are (3-(((4-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; (3-((benzenesulfonyl-(4-butyl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((4-butyl-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; and (3-(((4-dimethylamino-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
An especially preferred compound within the L Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is -CH2-X-CH2- wherein X is metaphenylene.
Another especially preferred compound within the L Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is phenyl; Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is -CH2-X-CH2- wherein X is metaphenylene.
Yet another especially preferred compound within the L Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is 4-(1-methyl-imidazolyl); Z is carboxy M is phenyl substituted at the 4-position with n-butyl; and Q is -CH2-X-CH2- wherein X is metaphenylene.
Yet another especially preferred compound with the L Group is the compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with dimethylamino, and Q is -CH2-X-CH2- wherein X is metaphenylene.
Another preferred group of compounds will the J Group comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C2-C4)alkylene-thienyl, -(C2-C4)alkylene-furanyl or -(C2-CH4)alkylene-thiazolyl.
A preferred group of compounds within the J Group, designated the M Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is (C1-C2)-X-O-(C1-C2)alkylene- and X is metaphenylene, said X being optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethoxy or methyl.
An especially preferred group of compounds with the M Group are (3-(((4-dimethylamino-benzyl)-(pyridine-3-sulfonyl)-amino)methyl-phenoxy)-acetic acid and (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.
An especially preferred compound within the M Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxyl; M is phenyl substituted at the 4-position with dimethylamino: and Q is -CH2-X-O-CH2- wherein X is metaphenylene.
Another especially preferred compound within the M Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with tert-butyl; and Q is -CH2-X-O-CH2- wherein X is metaphenylene.
Another preferred group of compounds within the FA Group, designated the N Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein G is Ar; K is (C2-C4) alkylene or n-propenylene; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridinyl, imidazolyl, pyrimidyl thienyl or thiazolyl, wherein Ar is optionally mono-, di-or tri-substituted with R3, R4 or R5; and Ms is Ar3, optionally mono-, di- or tri-substituted with chloro, fluro, methyl, mtehoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl.
An especially preferred compound within the N Group is trans-(3-(((3-3,5-dichloro-phenyl)-allyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
An especially preferred compound within the N Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is trans-n-propenylene, said M group being attached to the 1-position of the n-propenylene and said N atom being attached to 3-position of the n-propenylene; Ar is pyrid-3-yl; M is phenyl 3,5-disubstituted with chloro; Z is carboxy; and Q is CH2-X-CH2- wherein X is metaphenylene.
A preferred group of compounds within the N Group, designated the O Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Ar3 is phenyl optionally substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl.
A preferred group of compounds within the O Group, designated the P Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C5-C7)alkylene-.
Another group of compounds within the O Group, designated the Q Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-CH2- and X is metaphenylene.
Yet another group of compounds within the O Group, designated the R Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C2-C4)alkylene-X- and X is furanyl, thienyl or thiazolyl.
Yet another preferred group of compounds within the O Group, designated the S Group, comprises these compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C1-C2)-X-O-(C1-C2)alkylene- and X is metaphenylene.
Another preferred group of compounds within the FA Group, designated the T Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein G is Ar; K is thioethylene or oxyethylene, Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally substituted with up to three R3, R4 or R5; and M is Ar3, optionally mono-, di- or tri-substituted with chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
A preferred group of compounds within the T Group, designated the U Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A3 is phenyl.
A preferred group of compounds within the U Group, designated the V Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C5-C7)alkylene-.
Another preferred group of compounds within the U Group, designated the W Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -CH2-X-CH2- and X is metaphenylene.
Another preferred group of compounds with the U Group, designated the Y Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C2-C4)alkylene-X- and X is furanyl, thienyl or thiazolyl
Another preferred group of compounds within the U Group, designated the Y Group, comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Q is -(C1-C2)-X-O-(C1-C2)alkylene- and X is metaphenylene.
An especially preferred compound with the Y Group is (3-(((2-(3,5-dichloro-phenoxy)-ethyl)-(pyridine-3-sulfonyl)-amino)methyl)-phenoxy)-acetic acid.
An especially preferred compound within the Y Group is the compound, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein K is ethylenyloxy; said M group being attached to the oxygen atom of the ethylenloxy group and said N atom being attached to the 2-position of the ethylenyloxy group; Ar is pyrid-3-yl; M is phenyl 3,5-disubstituted with chloro; Z is carboxy and Q is -CH2-X-O-CH2- wherein X is a second phenyl ring and said CH2 and OCH2 substituents are situated in a meta substitution pattern on said second phenyl ring.
Another preferred group of compounds, designated the Z Group, comprises those compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein B is CH.
A preferred group of compounds within the Z Group comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is Ar, K is methylenyl, propylenyl, propenylenyl or oxyethylenyl; M is Ar3 or Ar4-Ar5; Ar3 is phenyl or pyridyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C7) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; Ar is phenyl, pyrazolyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar, Ar3, Ar4 and Ar5 are optionally substituted independently with up to three chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
Another especially preferred group of compounds within the Z Group comprises those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is CO; G is Ar, K is methylenyl, propylenyl, propenylenyl or oxyethylenyl; M is Ar3 or Ar4-Ar5; Ar3 is phenyl or pyridyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C7) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar, Ar3, Ar4 and Ar5 are optionally substituted independently with up to three chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
This invention is also directed to methods for treating vertebrates, e.g., a mammal, having a condition which presents with low bone mass comprising administering to said vertebrate, e.g., a mammal, having a condition which presents with low bone mass a therapeutically effective amount of a compound of Formula I, a prodrug thereof of a pharmaceutically acceptable salt of said compound or said prodrug. Preferably post-menopausal women and men over the age of 80 are treated. Also included are individuals regardless of age who have significantly reduced bone mass, i.e., greater than or equal to 1.5 standard deviations below young normal levels.
Yet another aspect of this invention is directed to methods for treating osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth an osteoporosis, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from osteoporosis an osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating osteotomy in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g. a mammal having undergone an osteotomy a bone restoration treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein a bone restoration treating amount is an amount of said Formula I compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug sufficient to restore bone in areas containing bone defects due to said osteotomy. In one aspect the Formula I compound, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to a site of osteotomy.
Yet another aspect of this invention is directed to methods for treating alveolar or mandibular bone loss in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from an alveolar bone or mandibular loss, an alveolar or mandibular bone loss treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., mammal suffering from bone loss associated with periodontitis, a bone loss associated with periodontitis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating childhood idiopathic bone loss is a child comprising administering to a child suffering from childhood idiopathic bone loss a childhood idiopathic bone loss treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating xe2x80x9csecondary osteoporosis,xe2x80x9d which includes gluococorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), by administering to said vertebrate, e.g., a mammal suffering from xe2x80x9csecondary osteoporosis,xe2x80x9d a xe2x80x9csecondary osteoporosisxe2x80x9d treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating glucocorticoid-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from gluocorticoid-induced osteoporosis, a glucocorticoid-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating hyperthyrodism-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from hyperthyroidism-induced osteoporosis a hyperthyroidism-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating immobilization-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from immobilization-induced osteoporosis, an immobilization-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating heparin-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from heparin-induced osteoporosis, a heparin-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from immunosuppressive-induced osteoporosis, an immunosuppressive-induced osteoporosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for treating a bone fracture in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from a bone fracture, a bone fracture treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect of this invention for treating a bone fracture the Formula I compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of bone fracture. In another aspect of this invention the Formula I compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is administered systemically.
Yet another aspect of this invention is directed to methods for enhancing bone healing following focal reconstruction, maxillary reconstruction or mandibular reconstruction in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal which has undergone facial reconstruction, maxillary reconstruction or mandibular reconstruction, a bone enhancing amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect of this method a Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of bone reconstruction.
Yet another aspect of this invention is directed to methods for treating prosthetic ingrowth in a vertebrate, such as promoting bone ingrowth into a bone prothesis in, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from prosthetic ingrowth, a prosthetic ingrowth treating amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for inducing vertebral synostosis in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal undergoing surgery for vertebral synostosis, a therapeutically effective amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for enhancing long bone extension in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal suffering from an insufficiently sized long bone, a long bone enhancing amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Yet another aspect of this invention is directed to methods for strengthening a bone graft i a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g., a mammal in receipt of a bone graft, a bone graft strengthening amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Additionally, a compound of Formula 1 a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug can be used as an alternative to bone graft surgery. In one aspect of this method of Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied locally to the site of the bone graft. In another aspect of this method a Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug is applied directly to the bone by injection or direct application to the bone surface.
A preferred dosage is about 0.001 to 100 mg/kg/day of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. An especially preferred dosage is about 0.01 to 10 mg/kg/day of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the augmentation of bone mass which comprise a bone mass augmenting amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of a condition which presents with low bone mass in a vertebrate, e.g., a mammal (including a human being), which comprise a low bone mass condition treating amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the local or systemic treatment of osteoporosis, bone fractures, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), which comprises a therapeutically effective amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of xe2x80x9csecondary osteoporosisxe2x80x9d, which includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which compositions comprise a xe2x80x9csecondary osteoporosisxe2x80x9d treating amount of a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise an osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for enhancing bone fracture healing in a vertebrate, e.g., a mammal (including a human being), which comprise a bone fracture treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of osteotomy in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrate, e.g. a mammal having undergone an osteotomy a bone restoration treating amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein a bone restoration treating amount is an amount of said Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt of said compound or said prodrug sufficient to restore bone in areas containing bone defects due to said osteotomy. In one aspect the Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to an osteotomy site.
This invention is also directed to pharmaceutical compositions for facilitating bone healing after an osteotomy in a vertebrate, e.g., a mammal (including a human being), comprising administering to said vertebrae, e.g., a mammal having undergone an osteotomy a bone healing amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. In one aspect the Formula 1 compound, prodrug thereof or pharmaceutically acceptable salt thereof is applied locally to an osteotomy site.
This invention is also directed to pharmaceutical compositions for the treatment of alveolar or mandibular bone loss in a vertebrate, e.g., a mammal (including a human being), which comprise an alveolar or mandibular bone loss treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of childhood idiopathic bone loss in a child which comprise a childhood idiopathic bone loss treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the augmentation of bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction in a vertebrae, e.g., a mammal (including a human being), which comprise a bone healing amount of a compound of the formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of bone loss associated with periodontitis in a vertebrate, e.g., a mammal (including a human being), which comprise a bone loss associated with periodontitis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of prosthetic ingrowth in a vertebrate, e.g., a mammal (including a human being), which comprise a prosthetic ingrowth treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for inducing vertebral synostosis or spinal fusion in a vertebrate, e.g., a mammal (including a human being), which comprise a therapeutically effective amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for enhancing bone union in a long bone extension procedure in a vertebrate, e.g., a mammal (including a human being), which comprise a bone mass augmentation treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of glucocorticoid-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise a glucocorticoid-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of hyperthyroidism-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise a hyperthyroidism-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of immobilization-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being), which comprise an immobilization-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of heparin-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being) which comprise a heparin-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to pharmaceutical compositions for the treatment of immunosuppressive-induced osteoporosis in a vertebrate, e.g., a mammal (including a human being) which comprise an immunosuppressive-induced osteoporosis treating amount of a compound of the Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
Yet another aspect of this invention is directed to combinations of the Formula 1 compounds, prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs and other compounds as described below.
Yet another aspect of this invention is directed to pharmaceutical compositions comprising a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug and for the use of such compositions for the treatment or prevention of conditions which present with low bone mass, including osteoporosis in a vertebrates, e.g., mammals (e.g., humans, particularly women) or the use of such compositions for other bone mass augmenting uses.
The combinations of this invention comprise a therapeutically effective amount of a first compound, said first compound being a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and a therapeutically effective amount of a second compound, said second compound being an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug such as an estrogen agonist/antagonist or a bisphosphonate.
Another aspect of this invention is directed to methods for treating vertebrates, e.g., mammals which present with low bone mass comprising administering to said vertebrate, e.g., a mammal having a conduction which presents with low bone mass.
a. an amount of a first compound, said first compound being a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and
b. an amount of a second compound, said second compound being an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug such as an estrogen agonist/antagonist or a bisphosphonate.
Such compositions and methods may also be used for other bone mass augmenting uses.
A preferred aspect of this method is wherein the condition which presents with low bone mass is osteoporosis.
Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously.
Another preferred aspect of this method is wherein the first compound is administered for a period of from about one week to about five years.
An especially preferred aspect of this method is wherein the first compound is administered for a period of from about one week to about three years.
Optionally the administration of the first compound is followed by administration of the second compound wherein the second compound is an estrogen agonist/antagonist for a period of from about three months to about three years without the administration of the first compound during the second period of from about three months to about three years.
Alternatively, the administration of the firs compound is followed by administration of the second compound wherein the second compound is an estrogen agonist/antagonist for a period greater than about three years without the administration of the first compound during the greater than about three year period.
Another aspect of this invention is a kit comprising:
a. an amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. an amount of an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug such as an estrogen agonist/antagonist or a bisphosphonate and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and
c. container means for containing said first and second dosage forms.
Yet another aspect of this invention is directed to pharmaceutical compositions comprising a compound of Formula 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and another bone anabolic agent (although the other bone anabolic agent may be a different Formula 1 compound), a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug and for the use of such compositions for the treatment of conditions which present with low bone mass, including osteoporosis in a vertebrates, e.g., mammals (e.g., humans, particularly women), or the use of such compositions for other bone mass augmenting uses. Such compositions comprise a therapeutically effective amount of a first compound, said first compound being a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and a therapeutically effective amount of a second compound, said second compound being another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
Another aspect of this invention is directed to methods for treating vertebrates, e.g., mammals which present with low bone mass comprising administering to said vertebrate, e.g., a mammal having a condition which presents with low bone mass.
a. an amount of a first compound, said first compound being a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt or prodrug thereof; and
b. an amount of a second compound, said second compound being another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
Such compositions and methods may also be used for other bone mass augmenting uses.
A preferred aspect of this method is wherein the condition which presents with low bone mass is osteoporosis.
Another preferred aspect of this method is wherein the first compound and the second compound are administered substantially simultaneously.
Another aspect of this invention is a kit comprising:
a. an amount of a Formula 1 compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. an amount of a second compound, said second compound being another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug in a second unit dosage form; and
c. container means for containing said first and second dosage forms.
Where used in any of the above methods, kits and compositions, certain bone anabolic agents, estrogen agonists/antagonists and bisphosphonates are preferred or espectially preferred.
Preferred bone anabolic agents include IGF-1, prostaglandins, prostaglandin agonists/antagonists, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, parathyroid hormone related peptides and active fragments and analogues of parathyroid hormone related peptides, growth hormones or growth hormone secretagogues and the pharmaceutically acceptable salts thereof.
Preferred estrogen agonists/antagonists include droloxifene, raloxifene, tamoxifen; 4-hydroxy-tamoxifen; toremifene; centchroman; levormeloxifene; idoxifene; 6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-ol; (4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)p(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)-methanone;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid;
2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol;
cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-(6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol; and
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline and the pharmaceutically acceptable salts thereof.
Especially preferred estrogen agonists/antagonists include droloxifene;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid;
2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol;
cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-(6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; and the pharmaceutically acceptable salts thereof.
Preferred bisphosphonates include, tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid and their pharmaceutically acceptable salts.
It will be recognized that prodrugs and pharmaceutically acceptable salts may be formed from the compounds used as the second compounds in the combinations of this invention. All of such prodrugs and pharmaceutically acceptable salts so formed are within the scope of this invention. Particularly preferred salt forms include droxloxifene citrate, raloxifene hydrochloride, tamoxifen citrate and toremifene citrate.
The phrase xe2x80x9ccondition(s) which presents will low bone massxe2x80x9d refers to a condition where the level of bone mass is below the age specific normal as defined in standards by the World Health Organization xe2x80x9cAssessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843xe2x80x9d. Included in xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d are primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis and immunosuppressive-induced osteoporosis. Also included is periodontal disease, alveolar bone loss, post-osteotomy and childhood idiopathic bone loss. The phrase xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d also includes long term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery.
The phrase xe2x80x9ccondition(s) which presents with low bone massxe2x80x9d also refers to a vertebrate, e.g., a mammal known to have a significantly higher than average chance of developing such diseases as are described above including osteoporosis (e.g., post-menopausal women, men over the age of 60).
Other bone mass augmenting or enhancing uses include bone restoration, increasing the bone fracture healing rate, replacing bone graft surgery entirely, enhancing the rate of successful bone grafts, bone healing following facial reconstruction or maxillary reconstruction or mandibular reconstruction, prosthetic ingrowth, vertebral synostosis or long bone extension.
The compounds and compositions of this invention may also be used in conjunction with orthopedic devices such as spinal fusion cages, spinal fusion hardware, internal and external bone fixation devices, screws and pins.
Those skilled in the art will recognize that the term bone mass actually refers to bone mass per unit area which is sometimes (although not strictly correctly) referred to as bone mineral density.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic), palliative and curative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the Formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors which, following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the Formula 1 compounds include but are not limited to substituents wherein the Z moiety is independently carboxyl and the free hydrogen is replaced by (C1-C4)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl) amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as b-dimethylaminoethyl), carbamoyl-(C1-C2) alkyl, N,N-di(C1-C2) alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3) alkyl.
Exemplary five to six membered aromatic rings optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur (i.e., X rings) are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
Exemplary partially saturated, fully saturated or fully unsaturated vive to eight membered rings optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen (i.e., Ar, Ar1 and Ar2) are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, osoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.
Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl.
Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.
Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
Exemplary bicyclic rings consisting of two fused independently partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, 1,4-benzodioxan, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
Exemplary tricyclic rings consisting of three fused independently partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indacenyl, biphenylenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, naphthothienyl, thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl and phenoxazinyl. It will be understood that the fully saturated and all partially unsaturated forms of these rings are within the scope of this invention. Further, it will be understood that nitrogen may be substituted as the heteroatom at any position, including a bridgeghead position, in the heterocyclic rings. Further still, it will be understood that sulfur and oxygen may be substituted as the heteroatom at any non-bridgehead position within the heterocyclic rings.
By alkylene is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompases the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene and heptylene.
By alkenylene is meant a hydrocarbon containing monounsaturation in the form of one double bond wherein said hydrocarbon is straight chain or branched and wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are ethenylene (or vinylene), propenylene, butenylene, pentenylene, hexenylene and heptenylene.
By alkynylene is meant a hydrocarbon containing di-unsaturation in the form of one triple bond wherein said hydrocarbon is straight chain or branched and wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are ethynylene, propynylene, butynylene, pentynylene, hexynylene and heptynylene.
By halo is meant chloro, bromo, iodo, or fluoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopenyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and oxtoxy.
As used herein, the term mono-N- or di-N,N-(C1-Cx)alkyl . . . refers to the (C1-CVx) alkyl moiety taken independently when it is di-N,N-(C1-Cx)alkyl . . . (x refers to integers and is taken independently when two (C1-Cx)alkyl groups are present, e.g., methylenethylamino is within the scope of di-N,N-(C1-Cx)alkyl).
Unless otherwise stated the xe2x80x9cMxe2x80x9d moieties defined above are optionally substituted (e.g., the mere listing of a substituent such as R1 in a subgenus or dependent claim does not mean that M is always substituted with the R1 moiety unless it is stated that the M moiety is substituted with R1). However, in the compounds of Formula 1, when K is a bond and M is phenyl, said phenyl group is substituted with one to three substituents. Additionally, in the compounds of Formula 1, when Ar or Ar1 is a fully saturated five to eight membered ring, said ring is unsubstituted.
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate, through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term xe2x80x9cpyridylxe2x80x9d means 2-, 3-, or 4-pyridyl, the term xe2x80x9cthienylxe2x80x9d means 2-, or 3-thienyl, and so forth.
The expression xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions xe2x80x9creaction inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular sterochemical or geometric configuration, giving rise to stereoisomers such as enantiomers and diastereomers; and configurational isomers such as cis and trans olefins and cis and trans substitution patterns on saturated alicyclic rings. All such isomers and mixtures thereof are included in this invention.
Hydrates and solvates of the compounds of this invention are also included.
DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA means ethylenediamine tetraacetic acid.
The methods and compounds of this invention result in bone formation resulting in decreased fracture rates. This invention makes a significant contribution to the art by providing compounds and methods that increase bone formation resulting in prevention, retardation, and/or regression of osteoporosis and related bone disorders.
Other features and advantages will be apparent from the specification and claims which describe the invention.
This invention is also directed to methods for treating glaucoma in a mammal suffering from glaucoma comprising administering to said mammal a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
This invention is also directed to methods for treating ocular hypertension in a mammal suffering from ocular hypertension comprising administering to said mammal a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.